Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia

Jeroen B. van der Net, Jorie Versmissen, Daniëlla M. Oosterveer, Joep C. Defesche, Mojgan Yazdanpanah, Bradley E. Aouizerat, Ewout W. Steyerberg, Mary J. Malloy, Clive R. Pullinger, John P. Kane, John J P Kastelein, Eric J G Sijbrands

Research output: Contribution to journalArticle

Abstract

Objectives: To investigate the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene as a potential modifier gene for coronary heart disease (CHD) in patients with familial hypercholesterolemia (FH). Background: The ALOX5AP gene is required for the synthesis of leukotrienes, a protein family involved in inflammatory responses. Recently, genetic variation in this gene was shown to be associated with myocardial infarction in an Icelandic and British population. Since FH is characterized by severely increased levels of plasma low-density lipoprotein (LDL) cholesterol levels, chronic inflammation of the arterial wall, and subsequent premature CHD, the ALOX5AP gene could be an important modifier gene for CHD in FH. Methods: In a cohort of 1817 FH patients, we reconstructed two four-marker haplotypes, previously defined in Icelandic (HapA) and British (HapB) individuals. The haplotypes were inferred with PHASE and the associations between the haplotypes and CHD were analyzed with a Cox proportional hazards model, adjusted for year of birth, sex, and smoking. Results: HapB had a frequency of 6.9% and 8.2% in the group without and with CHD, respectively, conferring a hazard ratio of 1.48 (95% CI 1.17-1.89, p = 0.001). This association was predominantly found in patients with LDL cholesterol levels above the median (HR 1.82, 95% CI 1.20-2.76, p = 0.005). HapA was not associated with CHD. Conclusion: We conclude that genetic variation in the ALOX5AP gene contributes to CHD risk in patients with FH. Our findings emphasize the important role of inflammation in the pathogenesis of early CHD in this disorder, particularly in patients with more severely raised LDL cholesterol levels.

Original languageEnglish (US)
Pages (from-to)472-478
Number of pages7
JournalAtherosclerosis
Volume203
Issue number2
DOIs
StatePublished - Apr 2009

Fingerprint

5-Lipoxygenase-Activating Proteins
Hyperlipoproteinemia Type II
Coronary Disease
Genes
Modifier Genes
LDL Cholesterol
Haplotypes
Arteritis
Leukotrienes
Proportional Hazards Models
Smoking
Myocardial Infarction
Parturition
Inflammation

Keywords

  • ALOX5AP
  • Coronary heart disease
  • Familial hypercholesterolemia
  • FLAP
  • Genetics
  • Lipoxygenase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

van der Net, J. B., Versmissen, J., Oosterveer, D. M., Defesche, J. C., Yazdanpanah, M., Aouizerat, B. E., ... Sijbrands, E. J. G. (2009). Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia. Atherosclerosis, 203(2), 472-478. https://doi.org/10.1016/j.atherosclerosis.2008.07.025

Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia. / van der Net, Jeroen B.; Versmissen, Jorie; Oosterveer, Daniëlla M.; Defesche, Joep C.; Yazdanpanah, Mojgan; Aouizerat, Bradley E.; Steyerberg, Ewout W.; Malloy, Mary J.; Pullinger, Clive R.; Kane, John P.; Kastelein, John J P; Sijbrands, Eric J G.

In: Atherosclerosis, Vol. 203, No. 2, 04.2009, p. 472-478.

Research output: Contribution to journalArticle

van der Net, JB, Versmissen, J, Oosterveer, DM, Defesche, JC, Yazdanpanah, M, Aouizerat, BE, Steyerberg, EW, Malloy, MJ, Pullinger, CR, Kane, JP, Kastelein, JJP & Sijbrands, EJG 2009, 'Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia', Atherosclerosis, vol. 203, no. 2, pp. 472-478. https://doi.org/10.1016/j.atherosclerosis.2008.07.025
van der Net, Jeroen B. ; Versmissen, Jorie ; Oosterveer, Daniëlla M. ; Defesche, Joep C. ; Yazdanpanah, Mojgan ; Aouizerat, Bradley E. ; Steyerberg, Ewout W. ; Malloy, Mary J. ; Pullinger, Clive R. ; Kane, John P. ; Kastelein, John J P ; Sijbrands, Eric J G. / Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia. In: Atherosclerosis. 2009 ; Vol. 203, No. 2. pp. 472-478.
@article{d6eb9c05e0ee42598ee252c0930cc55f,
title = "Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia",
abstract = "Objectives: To investigate the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene as a potential modifier gene for coronary heart disease (CHD) in patients with familial hypercholesterolemia (FH). Background: The ALOX5AP gene is required for the synthesis of leukotrienes, a protein family involved in inflammatory responses. Recently, genetic variation in this gene was shown to be associated with myocardial infarction in an Icelandic and British population. Since FH is characterized by severely increased levels of plasma low-density lipoprotein (LDL) cholesterol levels, chronic inflammation of the arterial wall, and subsequent premature CHD, the ALOX5AP gene could be an important modifier gene for CHD in FH. Methods: In a cohort of 1817 FH patients, we reconstructed two four-marker haplotypes, previously defined in Icelandic (HapA) and British (HapB) individuals. The haplotypes were inferred with PHASE and the associations between the haplotypes and CHD were analyzed with a Cox proportional hazards model, adjusted for year of birth, sex, and smoking. Results: HapB had a frequency of 6.9{\%} and 8.2{\%} in the group without and with CHD, respectively, conferring a hazard ratio of 1.48 (95{\%} CI 1.17-1.89, p = 0.001). This association was predominantly found in patients with LDL cholesterol levels above the median (HR 1.82, 95{\%} CI 1.20-2.76, p = 0.005). HapA was not associated with CHD. Conclusion: We conclude that genetic variation in the ALOX5AP gene contributes to CHD risk in patients with FH. Our findings emphasize the important role of inflammation in the pathogenesis of early CHD in this disorder, particularly in patients with more severely raised LDL cholesterol levels.",
keywords = "ALOX5AP, Coronary heart disease, Familial hypercholesterolemia, FLAP, Genetics, Lipoxygenase",
author = "{van der Net}, {Jeroen B.} and Jorie Versmissen and Oosterveer, {Dani{\"e}lla M.} and Defesche, {Joep C.} and Mojgan Yazdanpanah and Aouizerat, {Bradley E.} and Steyerberg, {Ewout W.} and Malloy, {Mary J.} and Pullinger, {Clive R.} and Kane, {John P.} and Kastelein, {John J P} and Sijbrands, {Eric J G}",
year = "2009",
month = "4",
doi = "10.1016/j.atherosclerosis.2008.07.025",
language = "English (US)",
volume = "203",
pages = "472--478",
journal = "Atherosclerosis",
issn = "0021-9150",
publisher = "Elsevier Ireland Ltd",
number = "2",

}

TY - JOUR

T1 - Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia

AU - van der Net, Jeroen B.

AU - Versmissen, Jorie

AU - Oosterveer, Daniëlla M.

AU - Defesche, Joep C.

AU - Yazdanpanah, Mojgan

AU - Aouizerat, Bradley E.

AU - Steyerberg, Ewout W.

AU - Malloy, Mary J.

AU - Pullinger, Clive R.

AU - Kane, John P.

AU - Kastelein, John J P

AU - Sijbrands, Eric J G

PY - 2009/4

Y1 - 2009/4

N2 - Objectives: To investigate the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene as a potential modifier gene for coronary heart disease (CHD) in patients with familial hypercholesterolemia (FH). Background: The ALOX5AP gene is required for the synthesis of leukotrienes, a protein family involved in inflammatory responses. Recently, genetic variation in this gene was shown to be associated with myocardial infarction in an Icelandic and British population. Since FH is characterized by severely increased levels of plasma low-density lipoprotein (LDL) cholesterol levels, chronic inflammation of the arterial wall, and subsequent premature CHD, the ALOX5AP gene could be an important modifier gene for CHD in FH. Methods: In a cohort of 1817 FH patients, we reconstructed two four-marker haplotypes, previously defined in Icelandic (HapA) and British (HapB) individuals. The haplotypes were inferred with PHASE and the associations between the haplotypes and CHD were analyzed with a Cox proportional hazards model, adjusted for year of birth, sex, and smoking. Results: HapB had a frequency of 6.9% and 8.2% in the group without and with CHD, respectively, conferring a hazard ratio of 1.48 (95% CI 1.17-1.89, p = 0.001). This association was predominantly found in patients with LDL cholesterol levels above the median (HR 1.82, 95% CI 1.20-2.76, p = 0.005). HapA was not associated with CHD. Conclusion: We conclude that genetic variation in the ALOX5AP gene contributes to CHD risk in patients with FH. Our findings emphasize the important role of inflammation in the pathogenesis of early CHD in this disorder, particularly in patients with more severely raised LDL cholesterol levels.

AB - Objectives: To investigate the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene as a potential modifier gene for coronary heart disease (CHD) in patients with familial hypercholesterolemia (FH). Background: The ALOX5AP gene is required for the synthesis of leukotrienes, a protein family involved in inflammatory responses. Recently, genetic variation in this gene was shown to be associated with myocardial infarction in an Icelandic and British population. Since FH is characterized by severely increased levels of plasma low-density lipoprotein (LDL) cholesterol levels, chronic inflammation of the arterial wall, and subsequent premature CHD, the ALOX5AP gene could be an important modifier gene for CHD in FH. Methods: In a cohort of 1817 FH patients, we reconstructed two four-marker haplotypes, previously defined in Icelandic (HapA) and British (HapB) individuals. The haplotypes were inferred with PHASE and the associations between the haplotypes and CHD were analyzed with a Cox proportional hazards model, adjusted for year of birth, sex, and smoking. Results: HapB had a frequency of 6.9% and 8.2% in the group without and with CHD, respectively, conferring a hazard ratio of 1.48 (95% CI 1.17-1.89, p = 0.001). This association was predominantly found in patients with LDL cholesterol levels above the median (HR 1.82, 95% CI 1.20-2.76, p = 0.005). HapA was not associated with CHD. Conclusion: We conclude that genetic variation in the ALOX5AP gene contributes to CHD risk in patients with FH. Our findings emphasize the important role of inflammation in the pathogenesis of early CHD in this disorder, particularly in patients with more severely raised LDL cholesterol levels.

KW - ALOX5AP

KW - Coronary heart disease

KW - Familial hypercholesterolemia

KW - FLAP

KW - Genetics

KW - Lipoxygenase

UR - http://www.scopus.com/inward/record.url?scp=62649140865&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=62649140865&partnerID=8YFLogxK

U2 - 10.1016/j.atherosclerosis.2008.07.025

DO - 10.1016/j.atherosclerosis.2008.07.025

M3 - Article

C2 - 18775537

AN - SCOPUS:62649140865

VL - 203

SP - 472

EP - 478

JO - Atherosclerosis

JF - Atherosclerosis

SN - 0021-9150

IS - 2

ER -